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- EMDB-43034: Alpha7-nicotinic acetylcholine receptor time resolved bound to ep... -
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Basic information
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Title | Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 | |||||||||
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![]() | ION CHANNEL / MEMBRANE PROTEIN / NICOTINIC RECEPTOR | |||||||||
Function / homology | ![]() sensory processing / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / acetylcholine receptor activity / dendritic spine organization ...sensory processing / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / acetylcholine receptor activity / dendritic spine organization / chloride channel regulator activity / acetylcholine binding / regulation of amyloid precursor protein catabolic process / acetylcholine-gated monoatomic cation-selective channel activity / acetylcholine receptor signaling pathway / positive regulation of amyloid-beta formation / negative regulation of amyloid-beta formation / plasma membrane raft / modulation of excitatory postsynaptic potential / response to amyloid-beta / positive regulation of excitatory postsynaptic potential / negative regulation of tumor necrosis factor production / toxic substance binding / monoatomic ion transport / monoatomic ion transmembrane transport / positive regulation of protein metabolic process / positive regulation of long-term synaptic potentiation / electron transport chain / synapse organization / response to nicotine / calcium channel activity / memory / cognition / intracellular calcium ion homeostasis / positive regulation of angiogenesis / calcium ion transport / monoatomic ion channel activity / amyloid-beta binding / postsynaptic membrane / postsynapse / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / learning or memory / periplasmic space / response to hypoxia / electron transfer activity / positive regulation of protein phosphorylation / neuron projection / iron ion binding / positive regulation of cell population proliferation / synapse / heme binding / signal transduction / protein homodimerization activity / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.29 Å | |||||||||
![]() | Burke SM / Noviello CM / Hibbs RE | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation. Authors: Sean M Burke / Mariia Avstrikova / Colleen M Noviello / Nuriya Mukhtasimova / Jean-Pierre Changeux / Ganesh A Thakur / Steven M Sine / Marco Cecchini / Ryan E Hibbs / ![]() ![]() Abstract: The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological ...The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 136.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 35.5 KB 35.5 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.1 KB | Display | ![]() |
Images | ![]() | 57.2 KB | ||
Filedesc metadata | ![]() | 6.8 KB | ||
Others | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() | 72.2 MB 136.8 MB 136.8 MB 72.3 MB 134.3 MB 134.1 MB 134.2 MB 69.2 MB 134.2 MB 134.1 MB 134.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8v8cMC ![]() 8ut1C ![]() 8utbC ![]() 8uzjC ![]() 8v80C ![]() 8v82C ![]() 8v86C ![]() 8v88C ![]() 8v89C ![]() 8v8aC ![]() 8v8dC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : Alpha7-nicotinic acetylcholine receptor time resolved bound to ep...
Entire | Name: Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 |
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Components |
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-Supramolecule #1: Alpha7-nicotinic acetylcholine receptor time resolved bound to ep...
Supramolecule | Name: Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrom...
Macromolecule | Name: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 type: protein_or_peptide / ID: 1 Details: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage) ...Details: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage) Number of copies: 5 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 67.220797 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI ...String: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI PNGEWDLVGI PGKRSERFYE CCKEPYPDVT FTVTMRRRTL YYGLNLLIPC VLISALALLV FLLPADSGEK IS LGITVLL SLTVFMLLVA EIMPATSDSV PLIAQYFAST MIIVGLSVVV TVIVLQYHHH DPDGGKMPKW TRVILLNWCA WFL RMKRPG EDKVRPACQH KQRRCSLACG RMACAGAMAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPP KLEDK SPDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLSPTHD EHLLHGGQPP EGDPD LAKI LEEVRYIANR FRCQDESEAV CSEWKFAACV VDRLCLMAFS VFTIICTIGI LMSAPNFVEA VSKDFAWSHP QFEKGG GSG GGSGGSSAWS HPQFEKGSGE GRGSLLTCGD VEENPG UniProtKB: Neuronal acetylcholine receptor subunit alpha-7, Soluble cytochrome b562 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 10 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: EPIBATIDINE
Macromolecule | Name: EPIBATIDINE / type: ligand / ID: 4 / Number of copies: 5 / Formula: EPJ |
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Molecular weight | Theoretical: 208.687 Da |
Chemical component information | ![]() ChemComp-EPJ: |
-Macromolecule #5: N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea
Macromolecule | Name: N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea type: ligand / ID: 5 / Number of copies: 5 / Formula: I34 |
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Molecular weight | Theoretical: 311.721 Da |
Chemical component information | ![]() ChemComp-I34: |
-Macromolecule #6: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 3 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 6.5 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |